Comprehensive Assessment Reveals Numerous Clinical and Neurophysiological Differences Between MECP2-Allelic Disorders

Authors

Davut Pehlivan
Chengjun Huang
Holly K Harris
Christine Coquery
Aditya Mahat
Mirjana Maletic-Savatic
Laurence Mignon
Sukru Aras
Daniel G Glaze
Charles S Layne
Leonardo Sahelijo
Huda Y Zoghbi
Matthew J McGinley
Bernhard Suter

Publication Date

2-1-2025

Journal

Annals of Clinical and Translational Neurology

DOI

10.1002/acn3.52269

PMID

39838601

PMCID

PMC11822789

PubMedCentral® Posted Date

1-21-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Male, Methyl-CpG-Binding Protein 2, Female, Rett Syndrome, Child, Adolescent, Adult, Young Adult, X-Linked Intellectual Disability, Child, Preschool, Electroencephalography, Prospective Studies, Sleep, Biomarkers

Abstract

OBJECTIVE: Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) result from under- and overexpression of MECP2, respectively. Preclinical studies using genetic-based treatment showed robust phenotype recovery for both MDS and RTT. However, there is a risk of converting MDS to RTT, or vice versa, if accurate MeCP2 levels are not achieved. The aim of this study was to identify biomarkers distinguishing RTT from MDS.

MATERIALS AND METHODS: We prospectively enrolled 11 MDS and 6 male RTT like (MRL) individuals for a panel of clinical and neurophysiological assessments over two visits, 8-10 months apart.

RESULTS: We identified numerous clinical and physiological features as promising biomarkers. MRL individuals exhibited large amplitude whole body tremor, midline stereotypies (vs. hand flapping at sides in MDS), earlier neuromotor regression, and earlier onset but less commonly refractory epilepsy. In the neurophysiological domain, we observed several marked differences in sleep physiology between MDS/MRL and typically developing (TD) individuals including reduced sleeping time, increased delta power during rapid eye movement (REM) sleep, decreased occipital alpha and increased brain-wide delta power during wakefulness, and reduced spindle density and duration. MRL individuals also had much lower delta power during NREM 2 and 3 stages than the TD group. We found differences in spindle duration in the temporal lobes and spindle amplitude in the frontal lobes between MDS and MRL.

DISCUSSION: Our study revealed distinct clinical features of MDS and MRL that can be monitored during a clinical trial and may serve as target engagement, disease progression, or safety biomarkers for interventional studies.